OBJECTIVES:
To analyze the importance of natural killer cells, their killer immunoglobulinlike
receptors (KIR) and genes in autoimmunity and in the immune surveillance against
infectious agents and stem cells transplantation. The characteristics and polymorphisms
of the KIR genes and receptors in the Brazilian population is described. SOURCES: Textbooks,
review articles and recent scientific articles are cited and listed in the references.
SUMMARY OF THE FINDINGS: KIR genes and haplotypes within a Brazilian
Caucasian population were surveyed and analyzed to assess the future relationship
of this system with diseases. Of 116 voluntary bone marrow donors, we identified
32 genotypes with frequencies of A and B haplotypes of 51 and 49%, respectively.
A comparative analysis was performed between these genotypes and those from
other populations. CONCLUSIONS: Innate immunity is an important antiinfectious barrier
in newborns. It is independent of both cellular and humoral immunity, can be
faster and confers great advantage in early age. At the same time, it stimulates
CD8 T lymphocytes to act and amplify the immunological protection network. Nevertheless,
as in the majority of situations in which immunity is activated, it can also
be harmful, damaging the body through autoimmune mechanisms or even, through
its absence, creating space for infectious agents to act free. Our study of
a control group for KIR genotype and haplotypes in Brazilian Caucasoids could
be used in future analyse of diseases related to these genes.

The immune system
is a network of cellular and humoral components with the function of "self/nonself"
discrimination. When it works well, it can destroy infectious agents, tumor
cells and non identical transplanted cells.

Natural killer
cells (NK) are an important part of this immune surveillance. They account for
around 10 to 20% of circulating lymphocytes. Morphologically, they are larger
than T and B lymphocytes, exhibiting granular cytoplasm and CD16 and CD56 surface
markers. They differ from the members of the adaptive immunity system by a fast
reaction, sometimes in few hours, during invasion by viruses or bacteria. In
contrast, T lymphocytes can take days to initiate an effective immune response,
even though they do have much in common with NK cells, especially in terms of
surface markers, cytotoxic effectors function mediated by secretion of cytokines,
perforins, granzymes and interferon γ (INFγ) and a close relationship
with dendritic cells (DC). Natural killer cells exhibit certain differences,
such as absence of the T cell receptor, which is the main molecule in Tlymphocyte
immune response. The latter must pass through the thymus to enter the circulation
to be effective in immune surveillance.1 The NK cells are thymusindependent,
and patients with NK deficiencies suffer from persistent viral infections, particularly
caused by herpes viruses. In such patients, these agents can only be eliminated
using antiviral drugs, even though they may have adaptive immunoresponse.2

When NK cells
are isolated from blood they are capable of destroying certain types of targetcell.
This baseline level increases by 20 to 100 times in response to exposure to
interferon α (INFα), interferon β (INFβ) and
IL12 produced by macrophages in response to viral agents. These lymphokines
can activate NK cells to destroy infectious agents immediately or when CD8 T
lymphocytes initiate their activities. Interferonα and INFβ
promote the cytotoxic effects of NK cells, while IL12 stimulates cytokine
production, including INFγ, creating a positive feedback process
of both types of cells in the infected tissue. The manifestation of this is
that NK cells predominate during the onset of infections, with relation to INFγ
production, activating the macrophages to secrete lymphokines which in turn
start the adaptive immune response with the arrival of T lymphocytes. When they
start to work, NK cells may reduce activity in response to production of IL10
by T lymphocytes.2

Natural killer
cells have a large number of surface receptors, which are also present in certain
Tlymphocyte and are responsible for the identification of infectious agents
and abnormal cells. The class I major histocompatibility complex molecules,
participate in this process by their human leukocyte antigen (HLA), important
molecules in understanding the function of NK cells.3 These proteins
are also of great importance in the recognition of antigens by T lymphocytes,
although in a different manner from what happens with the NK cells. The T lymphocytes
recognize antigenic peptides that are exposed on the surface of HLA molecules
in antigen presenting cells by the T cell receptors. After this, lymphocytes
are active, producing lymphokines and sending stimulatory signals to other immune
system cells. In contrast, the NK cells recognize infected, abnormal or transplanted
cells by the "absence or presence" of HLA molecules on their surfaces. Therefore,
we can understand the HLA system as being the helper of two important "masters"
in defense and immune surveillance: the NK cells of innate immunoresponse and
the cytolytic T lymphocytes of adaptive immunoresponse.

At this point
we should mention the "missingself recognition" hypothesis, i.e., the
recognition of reduced or even absent expression of HLA molecules in infected
cells and in tumor cells or recognition of transplanted cells with foreign or
different HLA molecules, activating the NK cells which become aggressive and
potentially destructive.4,5 Therefore, the NK cells' role in immune
surveillance is dependent on appropriate and specific concentrations of HLA
molecules on the surfaces of other targetcells. In contrast, normal cells
which have normal levels of identical HLA molecules on their surfaces are recognized
by NK cells which generate an inhibition signal, preventing their destruction.6

The NK cells can
be activated and become cytotoxic as a result of exaggerated expression of ligands
for activation receptors on the targetcellsurface.5 In
this manner, NK cells can perform immune surveillance both by recognition of
reduced or absent expression of HLA molecules on targetcells and in response
to imbalances between activation and inhibition signals mediated by receptors
in the NK cells, known as killer immunoglobulinlike receptors (KIR). These
protein receptors are important in the destruction of abnormal cells and are
the expression of a cluster of genes identified as the KIR genes.

Innate immunity
is of great importance in pediatrics. Many infectious diseases can be effectively
neutralized even before the adaptive immune system has started. In certain diseases
with abnormal or low expression on the cell surface  such as on viral
infected and on tumors cells  the absence of an inhibition signal, in
addition to preventing inhibition itself, allows activation of the NK cells.7,8
On the other hand, there are also autoimmune diseases that are influenced by
NK cell activation and inhibition, and some patients can be protected or not
by the innate system after receiving bone marrow transplantation (BMT) to treat
leukemia (Figure 1).

Nomenclature
and polymorphisms of KIR genes and receptors

Natural killer
cells circulate in the blood in a practically activated state, ready to attack
infected tissues as soon as macrophages sound the alarm. The NK cells are maintained
in this state by a system of receptors which release activation or inhibition
signals.8

The nomenclature
of NK cell receptors is based on their extracellular and intracellular structure
(Figure 2). These molecules are similar to immunoglobulins
with two or three extracellular domains (2D and 3D) used to bind to polymorphic
determinants of the HLAA, B and C systems, a transmembrane (TM) region
and a cytoplasmic tail (CT), which may be short (S) or long (L). The names used
for the different KIRs and the sequences of their respective genes and alleles
can be accessed on the KIR database (http://www.ebi.ac.uk/ipd/kir).9

The CT and TM
regions control functional activity. Molecules with short tails (S) are activating,
while long tails (L) are inhibitory (with the exception of KIR2DL4). Molecules
with the long tail have one or two immunoreceptors with an immune tyrosinebased
inhibitory motif (ITIM). In contrast, short tail receptors do not have ITIM,
but a positivelycharged amino acid in the TM domain, wich allows interaction
with the DAP12 accessory molecule, releasing an activation signal via
an immunoreceptor tyrosinebased activation motif (ITAM). Therefore, the
KIR2DS1 receptor is a molecule with two extracellular domains and a single CT
 short and activating.

The KIR gene family
consists of fifteen genes (KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5A, KIR2DL5B,
KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL1, KIR3DL2, KIR3DL3 and KIR3DS1),
and two pseudogenes (KIR2DP1 and KIR3DP1), located in a region around 150 Kb
from the leukocyte receptor complex (LRC) on chromosome 19q13.4. The different
KIR genes exhibit great molecular similarity with each other and have originated
from one ancestral gene by a series of duplications, recombinations and mutations.
The basic KIR gene structure is a nineexon unit that represents the ancestral
gene.10

More than 100
different genotypes were detected by an international collaborative study.10
We found 32 genotypes in 116 Brazilian Caucasoids, the two most common of which
have frequencies of 24 and 13.80% (Figure 3). The same genotypes
were also the most prevalent in other studies.11

The KIR genes are
inherited in blocks, or haplotypes, as are the HLA genes. Although there are
a large number of KIR haplotypes, some are more prevalent, including the A and
B haplotypes (Figure 4). The A haplotype has seven loci and
its major characteristic is increased expression of inhibitory genes or receptors.
It is defined by the presence of KIR2DL1, KIR, KIR, KIR, KIR and KIR. The only
stimulatory receptor in the A haplotype is KIR2DS4. The B haplotype has several
combinations of KIR, KIR, KIR, KIR, KIR and KIR. The B haplotype has more activating
genes, and is defined by the presence of KIR2DL2 and absence of KIR3DL1 and
KIR2DL3.12,13 The genes KIR and KIR are present in both haplotypes,
and are known as structural or framework genes. In certain haplotypes, we may
observe the absence of one of the framework genes.14

Studies suggest
that NK cells do not react against other cells in the body under normal conditions.
Therefore, NK cells that do not express inhibitory receptors that recognize
selfHLA are unresponsive to and relatively tolerant to autologous cells.14
Expression of KIR is restricted to NK cells and certain T cells, known as NKT.

Natural killer
cell receptor ligands

The ligands for
KIR receptors are the class I HLA molecules (HLAA, B and C). The receptors
KIRD2DL2, KIRD2DL3 and KIRD2DS3 recognize certain HLAC molecules, identified
as members of group 1 (HLAC1). In counterpoint, the receptors KIR2DL1
and KIR2DS1 recognize group 2 (HLAC2) (Table 1). Groups
1 and 2 are distinguished by a dimorphism at position 80 of helix of the HLAC
molecule.15 Both forms are characterized by the presence of Ser77/Asn80
and Asn77/Lys80, and there is a certain hierarchy to the interaction of KIR
with HLAC molecules, been the interaction KIR2DL1C2 stronger than
KIR2DL3C1.

After a BMT, the
donor's NK cells that express only receptors for group C2 may lyse the patient's
group C1 homozygous targetcells. The same can happen if the donor is homozygous
for C2, and the receptor, homozygous for C1.

The HLAC,
the HLAB locus can also be divided into two groups: Bw4 and Bw6. The KIR3DL1
interacts with HLAB molecules if they have Bw4 serology, and, if these
have isoleucine (Ile) in position 80, there is greater inhibition of NKmediated
lysis. There are no known high affinity interaction with Bw6 molecules.16
The KIR2DL4 molecule binds to HLAG, which is a nonclassical HLA
type with little polymorphism and which is expressed in endothelial cells of
the thymus, fetal trophoblasts and cornea. Resting NK cells can be stimulated
to produce cytokines and chemokines by soluble HLAG. The KIR2DL4 gene
is a framework gene found in almost all individuals, although in around 50%
of people it is not expressed, suggesting that this gene could be subjected
to some type of selection. Therefore, if we assume that the KIR2DL4HLAG
interaction is physiologically relevant, it is also possible to suppose that
the presence of alleles that do not express it is due to some type of disadvantage
under certain conditions.

It is important
to point out that interactions between KIR and its HLA ligands can be modified
by peptides located in the Tcell receptor molecule binding region. Of
interest is the interaction between KIR3DL2 and HLAA3 and A11.

Laboratory
identification of the KIR genes

Blood samples
were collected to determine the distribution of the KIR genotypes and haplotypes
in a Brazilian Caucasoid population. The samples were collected in EDTA and
DNA extracted using the saltingout procedure.17 The DNA samples
were analyzed using polymerase chain reaction with specific primers (PCRSSP)
for 15 KIR genes.

The PCR primer
sequences were based on earlier publications.18 The amplification
products were viewed on a transilluminator with ultraviolet light, after electrophoresis
in agarose gel at 1%, containing ethidium bromide and typed according to their
size. A sample of such assay is shown in Figure 5.

The KIR genes
were also typed by sequencespecific oligonucleotides (PCRSSO) using
LabtypeSSO® reagents (TeppnelUnited States).

Alleles of the
HLACw system were also determined using PCRSSP.19

Results obtained
with the two methods (PCRSSO and PCRSSP) for the 116 blood samples
of the mentioned Brazilian Caucasoid population were absolutely identical, with
no differences between both methods (results not shown).

Comparison
of KIR genes of a Brazilian Caucasian population with other populations

The frequency
of the KIR genes of the 116 Brazilian Caucasoid was compared with those of other
populations.2025 The Brazilian, English and Argentine Caucasian
populations exhibit similar frequencies of the KIR genes (Table
2). Significant differences exist between the indigenous populations of
Argentina and Mexico, when compared with the Caucasoid populations. The KIR2DS3
activator gene in particular is different, since, either they do not have this
allele, or they have it in low frequency, in common with certain oriental populations
(Chinese and Japanese). The same KIR2DS3 have an intermediate frequency in the
Caucasoid populations, in contrast with 81% observed among Australian aboriginal
populations (Table 2).
There are other differences in relation to other populations, demonstrating
the different distribution of polymorphism for these markers and predicting
differences in innate immune response between populations.

Among Caucasoids,
the A and B haplotypes are distributed similarly.12,13 Of the 116
Brazilian Caucasoid donors, we found 51 and 49% of the A and B haplotypes, respectively.

One feature of
interest is the difference in the frequency of haplotypes between certain populations.
For example, the presence of the A haplotype is at an average of 75% in Japanese,
Han Chinese and Korean populations, but at just 13% in Australian aboriginal
populations.2426

KIR and diseases

The diversity
of frequencies of the KIR and HLA haplotypes in certain populations indicates
that certain individuals should have different levels of protection against
certain diseases.

Analysis of mRNA
and protein expression demonstrates that each NK cell clone in any given person
does not express all of the KIR genes identified in their genome, but a random
combination of them. Therefore, each individual has a repertoire of different
NK cells with variable expression of KIR molecules on their surfaces.27

Some authors have
proposed a model for classifying KIR/HLA combinations in terms of the predicted
activating or inhibitory tendencies of the NK cells.28,29 At one
extreme of the spectrum are the AA haplotypes, with their inhibitory tendency,
while at the other extreme are the BB haplotypes, with their inheritance of
a tendency to activation. Genotypes with inhibitory receptors and deficient
HLA ligands tend towards increased activation, with few NK cells under inhibitory
control. This appears to be a valid model for analyzing the risk of disease,
but we need more evidences for its validation. On the other hand, any model
that one wishes to organize in order to understand the relationships between
the KIR/HLA genotypes, must take into consideration the fact that some individuals
who have truncated variants of KIR2DS4 and KIR2DL4 within the A haplotype do
not express activating KIR molecules on the surface of their NK cells. Nevertheless,
they apparently have normal innate immunity. In accordance with these studies,
the hypothesis that at least one stimulatory receptor must exist no longer applies
to NK cells. Furthermore, those NK cells that do not express inhibitory receptors
that recognize selfHLA are apparently unresponsive and relatively tolerant
to autologous cells. The mechanism responsible for this effect is unknown, but
it is important to point out that inhibitory receptors that recognize the HLA
in their cells could have a positive role in the maturation of NK cells, giving
them a license to kill.30

In summary, the
balance between inhibition and activation means that the NK cell can help the
body in its natural immune surveillance, even before acquired immunity participates.
Infectious agents are eliminated or partially destroyed by the action of the
NK cells. Furthermore, there are other pathologies in which these systems have
equal importance, such as certain autoimmune diseases, tumors, preeclampsia
and recurrent miscarriages. There have been suggestions that activated KIR can
recognize class I HLA molecules that contain peptides related to certain pathologies
or even other types of ligand that serve to identify abnormal cells.

HIV

The innate and
adaptive immune systems are important during several stages of the HIV infection,
including in its progression. They are positively important in defense against
acute infection, and can even limit disease progression.

Natural killer
cells can lyse, in vitro, targetcells infected with HIV. Defects
in NK cell function can be associated with the disease progression. It is known
that HIV reduces HLA expression, and this activates NK cells to lyse targetcells.
Nevertheless, it is also known that the virus reduces expression of the HLAA
and B molecules, but may maintain HLAC expression, helping it to evade
recognition by the NK cells.31

Analysis of HLAB
alleles in infected individuals has demonstrated that homozygosis for HLABw4,
a ligand for KIR3DL1 and probably also for KIR3DS1, is associated with a slow
decline in CD4+ T lymphocyte counts, which are cells that make it possible to
know the progression of infection.32 Furthermore, analysis of more
than 1,000 individuals infected with HIV demonstrated that those with the KIR3DS1
genotype and a subtype of the HLABw4 allele that has Ile in position 80
on the heavy chain (Bw4Ile80) deteriorate more slowly than those in whom the
KIR/HLA activator combination is absent. Indeed, KIR3DS1 in the absence of this
specific Bw4 is not protective. A synergistic effect between the two is needed
for the beneficial effect. Nevertheless, the presence of an NK activator program
appears to be of benefit in limiting or delaying onset of the disease. It has
been suggested that the NK cell receptor (KIR3DS1) interacts with HLAB
Bw4Ile80 which contains HIV peptides, activating the NK cells to eliminate
the infected cell. In the same population of infected patients, it was observed
that the KIR3DS1/Bw4Ile80 combination had a delayed risk of opportunistic infections.33

Several different
studies have tried to find the reasons why some sex professionals do not become
seropositive. Although they have not found a complete answer, it appears clear
that the immunogenetics involved, translated into the ability to block the entrance
of HIV and the resulting seroconversion, are not the same that control disease
progression. In a study carried out in Abidjan, in the Ivory Coast, it was demonstrated
that exposed professionals who were seronegative often exhibited inhibitory
KIR genes in the absence of their cognate HLA genes, stimulating the activation
of NK cells with resulting protection against disease progression. These exposed
and seronegative women also had a greater frequency of KIR genotypes with more
activating receptors.34

Hepatitis C

One hundred and
seventy million people have the hepatitis C virus (HCV) and they may either
be cured or become chronically infected. The second class of patients has antiHCV
antibodies and HCVRNA in circulation and may progress to cirrhosis and
hepatoma. Patients are considered cured if the viral genome cannot be detected
in circulation for at least 2 years.

There is a theoretical
hypothesis that the response of innate immunity due to NK cells may stimulate
maturation of the dendritic cells. These, in turn, would activate the adaptive
immunoresponse by T lymphocytes, making possible an effective attack against
cells infected with HCV.

It has been demonstrated
that the subset of patients that cure had a high frequency of homozygosis for
group 1 HLAC and of homozygosis for KIR2DL3. This allele's affinity for
binding to HLAC is less than that of KIR2DL2 or KIR2DL1 for their ligands.
These findings could be related to a beneficial effect from inhibition, allowing
greater chances for stimulation of activating receptors. Patients with lighter
viral loads are also benefited by this combination of homozygosis.28

The results described
above encourage the idea that there may be a quantitative model of NK cell programming,
dependent on the functional differences between heterozygosis and homozygosis,
both for the KIR genes and their HLA ligands. The increased inhibition favors
activation and may benefit patients.

The significance
of NK cells for bone marrow transplantation

Immunological
reactivity after BMT is important. In order to reduce the chances of rejection,
myeloablation is used, which is to say, destruction of the patient's bone marrow
by chemotherapy. This procedure makes it possible to destroy the patient's lymphoid
tissues and their leukaemic tumor cells and makes space for the transplanted
marrow. Graft versus host disease (GVHD) is expected in a large proportion of
cases, being caused by CD8 T lymphocytes from the donor, which, in particular,
attack the intestine, skin and liver of the transplant patient. This takes place
after a lymphokine "storm" resulting from the myeloablative destruction, and
also dependent on HLA disparity between donor and recipient. Therefore, it would
be ideal to transplant patients with T lymphocytedepleted bone marrow,
reducing the risk of GVHD and any discrete class I HLA incompatibility. This
small disparity or alloreactivity serves to stimulate the donor's NK cells and
CD8 T lymphocytes to perform an attack against the patient's bone marrow, eliminating
leukemic cells (the graft versus leukemia effect) and residual marrow tissue.
Among the advantages of discrete alloreactivity are the immunological recovery,
the reduction of relapses and myeloablative chemotherapy.35

When transplants
are performed without graft lymphocyte depletion, the presence of activating
KIR in the donor provokes immunological reaction, whereas, when present in the
recipient it induces tolerance.

An increase in
acute GVHD was identified with KIR2DS3 donors in unrelated HLA identical donor
transplants and in cases where the donor had more than four activating KIR in
haploidentical transplants.

With the intention
of simplifying analyses of effectiveness, authors have grouped patients into
A and B haplotypes, where the first has more inhibitory KIR genes, and the second
more activating genes, and also to make it possible to observe whether HLAC1
and C2 ligands could also be used to evaluate the best KIRHLA compatibility
for BMT in leukemia patients.35 With relation to the A and B haplotypes,
they examined the donorrecipient relationship, considering the homozygous
AA group (with the greatest number of inhibitory genes) when only genes of group
A were present. All other individuals had one or more genes specific to the
B haplotypes. These could be AB heterozygotes or BB homozygotes, always expressing
stimulatory KIR genes. Approximately 28 and 30% of donors and recipients, respectively,
had the AA haplotype, where all others had, at least, one B haplotype. A survival
analysis of 202 patients indicated a discrete, and not significant tendency
to lower survival among AA patients receiving BX grafts. Nevertheless, in 113
patients with myeloid leukemia, a beneficial effects was demonstrated when BX
patients received grafts from AA donors. In contrast, survival is 3.8 times
worse for AA patients given BX grafts (p = 0.046). In other words, B haplotypes
(with more stimulatory genes) in the donor are prejudicial to this type of transplant,
while their presence in the recipient may be of benefit. These results were
analyzed and shown to be independent of patient age and disease stage.36

The combination
of BX donor and AA recipient was considered a risk factor for disease relapse
(myeloid leukemia) and acute GVHD degrees IIIV. In a group of 112 transplanted
patients, the incidence of acute GVHD was 46% in AA recipients with BX donors;
10% for AA recipients with AA donors; 20% for BX recipients with AA donors and
30% when both recipient and donor were BX.

The most dominant
ligands for the KIR receptors are the HLAC molecules. The difference between
the C1 and C2 ligands is that C2 produces stronger inhibition than C1. Therefore,
the same study divided the transplanted patients into the two groups in which
the recipients and their HLAidentical donors were C2. Recipients without
C2 alleles were defined as C1 homozygotes (C1C1). Recipients with C2 alleles,
including C2 homozygotes, were defined as C2CX. Surprisingly, the combination
of BX donor and AA recipient was only identified as a risk factor for acute
GVHD in C1C1 transplants, and not in C2CX. When the effect of the HLAC
type was analyzed alone, a mild tendency to risk of GVHD was detected in C1C1
cases, but not in C2C2.

In summary, the
best survival rates among transplanted myeloid leukemia patients is associated
with group B KIR being present in the recipient and absent in the donor. The
worst survival rates are observed when the donor has group B and the recipient
does not. This last combination is also related with increased relapse and acute
GVHD rates. However, these deleterious effects were only seen when donor and
recipient were homozygotes for the ligand KIRC1.

Autoimmunity

Several mechanisms
are hypothesized to explain the participation of NK cells in autoimmunity. Inappropriate
activation or lack of inhibition may be responsible for the pathogenic function
with the help of active T cells. Scleroderma is a disease involving tissue fibrosis,
inflammation and vascular damage. Recent study describes an association with
the NK cell activators KIR2DS1 and or KIR2DS237. Another interesting
example of this effect can be seen in psoriasis arthritis, where KIR2DS1 and/or
KIR2DS2 confer a high risk of the disease when the inhibitory receptors KIR2DL1
and KIR2DL2/3 are absent. A recent proposal suggests a model of susceptibility
to this disease due to the presence of homozygosis for HLAC ligands, minimizing
inhibitory signals and producing strong activation.38

A similar situation
has been identified in rheumatoid vasculitis, where risk is associated with
the presence of KIR2DS2. In a similar manner, diabetes type I is associated
with an increase in KIR2DS2/HLA ligands in the presence of inhibitory interactions.
The authors suggest a model in which the KIR function are secondary but provokes
low affinity for the T lymphocytes responsible for autoimmunity.39

Psoriasis vulgar
(PV) is a chronic inflammatory skin disease, the pathogenesis and genetic influence
of which remain unclear. Earlier studies have suggested an association between
this pathology and KIR2DS1 receptors and with HLAC0602, where people with
the second of these alleles have a 10 times greater chance of suffering from
PV. In the Brazilian Caucasian population, we found the Cw0602 allele in 26.5%
of the patients with PV, compared with just 5.4% of the controls (p < 0.001).
The KIR2DS1 did not reach statistic significance in prevalence.

With relation
to the KIR2DS1 activating gene, some publications have shown that it is statistically
more prevalent among PV patients than healthy controls.40 Other studies
intend to demonstrate that PV is a disease in which these activating KIR receptors
are present in the absence of their homologous HLA ligands. Therefore, in addition
to other environmental factors, PV is the result of a balance between activating
and inhibitory genotypes where activation predominates.37

Conclusions

The intention
of this article was to introduce a summary of the current knowledge about innate
immunity and its relationship with patients' immune surveillance. The importance
of this in pediatrics can be anticipated for premature patients, newborn infants
and for all of those who have not developed solid acquired immunity. The NK
cells, their receptors and genes are part of maintaining good health, especially
during this stage of life, when acquired immunity is not well effective. The
combination of these genes and receptors are partners for pediatricians, when
they prefer to wait for recovery, before given antibiotics early in the onset
of an infection. It is during this period of waiting for recovery that innate
mechanisms participate and, in the majority of times, they manage to overcome
the infectious agents. . With this review we show the Immunogenetic bases of
the KIR/HLA system that has recently been identified as of importance for the
prevention of infection, in bone marrow transplants and autoimmunity. The results
of the KIR genes and haplotypes frequencies in a Brazilian Caucasian control
group were also presented.

Acknowledgements

We are grateful
to the group of the Immunology Service at the Hospital de Clínicas de
Porto Alegre.